Chemical methods will be developed for the synthesis of four classes of pyrimidine nucleosides containing substitutions in both the sugar moiety and in the aglycon which may exhibit selective activity against several herpes viruses and against human tumors with minimal toxicity against normal cells. The basis of this specificity may be the nonspecific nucleoside kinase(s) carried or induced by the viruses or reported to be present in human tumor cells which could metabolize these compounds to active drugs. Some of these target nucleosides with good leaving groups may exert their biological effects by undergoing neighboring group displacement reactions in vivo ("masked precursors") to liberate the active drug. On the basis of the findings at this Institute that: (a) some of the 2'-fluoro-5-substituted-ara-C's synthesized under this grant exhibit exceptionally marked antiherpetic activity both in vitro and in vivo with little or no toxicity to normal cells, and, in addition, (b) that one of these compounds, FIAC, was shown in preliminary studies to have a specific cytotoxic effect on several human tumor cell lines without affecting the replication of normal human fibroblasts or lymphocytes in culture: it is proposed to develop chemical methods for the synthesis of six classes of nucleosides for evaluaton as potential antiviral and antitumor agents. Several glucuronides of anticancer nucleosides will be prepared. These nucleoside-beta-glucuronides are expected to undergo enzymatic cleavage in vivo in tumor tissue rich in beta-glucuronidase to liberate potent drugs.